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* Emma Children’s Hospital,
Laboratory for Experimental Immunology, and
Department of Medical Microbiology, Section of Clinical Virology, Academic Medical Center, and
Department of Clinical Viro-Immunology, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Functionally distinct CD8+ T cell subsets can be distinguished with combinations of phenotypic markers such as CD45RA/CD45R0, the costimulatory receptors CD28 (4), CD27 (5), and the chemokine receptor CCR7 (6). Naive CD8+ T cells express CD45RA (but not CD45R0) as well as CD28, CD27, and CCR7. Viral infection induces a massive expansion of specific CD8+ cells and rapid up-regulation of the cytolytic molecules perforin and granzyme B (7). During acute infection these cells express CD45R0, CD38 and HLA-DR, CD28, and CD27, whereas later in infection CD28 and CD27 may become down-regulated (8). In healthy individuals two prevalent types of resting primed (memory) T cells can be discerned. CD45R0+CD28+CD27+ T cells that have the ability to secrete IL-2, IFN-
, TNF-
, and IL-4 and contain virus-specific CTL precursors (9). A second primed population can be characterized by CD45RA expression with concomitant absence of the costimulatory molecules CD27 and CD28 and of CCR7. This CD8+CD45RA+CD27- population can secrete IFN- and TNF- but not IL-2 or IL-4, and abundantly expresses CD95 ligand, perforin, granzyme B, and shows high cytolytic activity without in vitro prestimulation (10). In healthy individuals a high degree of variation in the subset composition of the circulating CD8+ T cell population is observed. Although the way in which this variability is generated is unknown, recent studies have suggested that particular viruses may preferentially be associated with certain phenotypes of virus-specific T cells in latency (11).
To directly address this question, the relationship between CD8+ T cell subset composition and common viral infections of childhood, i.e., EBV, CMV, varicella-zoster virus (VZV),3 and measles-mumps-rubella (MMR) vaccinations was studied. Both EBV and CMV are herpesviruses that infect the vast majority of humans, following a bimodal pattern of infection with peaks during early childhood and late adolescence, being defined to a large extent by socioeconomic factors (12, 13). In The Netherlands, a cross-sectional serum study in 1991 had shown that 40% is EBV-seropositive at 10 years of age increasing to 98% at 30 years, while CMV immunity is detected in 
30 and 50%, respectively (14). Infection with these viruses early in life is most often asymptomatic, while infection later in life is a self-limiting disease more often associated with clinical symptoms (12). On the other hand, chickenpox (varicella) is a common disease of childhood caused by primary infection with VZV, a highly contagious herpesvirus with attack rates of >85% in susceptible contacts in the temperate climate under 7 years of age (15, 16, 17). VZV vaccine is not presently in use in The Netherlands. However, live-attenuated measles, mumps, and rubella virus are used for routine MMR vaccination in The Netherlands with a coverage of >98% of the young children and high seroconversion rates regardless of intercurrent infections or fever (18, 19, 20, 21, 22). Our analyses show that CMV is the main, if not the only, factor responsible for the expansion of cytolytic CD8+CD45RA+CD27- T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Children and young adolescents under the age of 18 years being routinely analyzed for pre- or perioperative procedures were included in the study (n = 220; control cohort; Table I). We also included patients with a diagnosis of a (sub)acute viral infection and those tested or admitted for a suspected viral infection of the upper and lower respiratory, gastrointestinal, or urogenital tract (n = 58). Those with an acute CMV infection were asked for consent to be followed-up with regular blood tests (n = 16). In 10 families all members who underwent venipuncture for HLA typing in a search for an HLA-identical family donor for a related sibling (not included in the pedigrees) were also tested for viral serology against various common viruses after written consent was obtained. Data for infants under the age of 6 mo were not included to avoid the interference of (low titer) maternal Abs in our study. In each age category 15–30% of the healthy controls were of African, Caribbean, or Mediterranean origin. The remainder was of Caucasian origin. Informed consent for the research purpose described was obtained from the parents of the children included in the studies as approved by the institutional medical ethical committee.
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Immunophenotyping of PBMC fractions from the blood of individuals was performed as described below. In the same blood samples, T cell proliferation tests were performed to define functional activity in vitro and thus exclude unforeseen immune dysfunction. Serology was performed in blood drawn at the same moment as the immune tests.
Laboratory tests for EBV, CMV, VZV, and MMR serology
Specific IgM and IgG against the EBV-viral capsid Ag was determined by indirect immunofluorescence and Abs to Epstein-Barr nucleic acid by anticomplement immunofluorescence (Gull Laboratories, Salt Lake City, UT). Specific IgG Abs to CMV and rubellavirus were defined by Imx assays (Abbott Diagnostics, Amstelveen, The Netherlands). IgM to CMV and IgG to VZV were defined by VIDAS tests (Biomerieux, Lyon, France). Specific IgG to measles and mumps was defined by ELISA (Virotech, Russelheim, Germany). All tests were performed following the instructions of the manufacturers. Serology data for EBV, CMV, VZV, measles, mumps, and rubella in the control individuals are summarized in Table I. The serologic characteristics of the cohort are in agreement with previous studies (14).
Lymphocyte subsets and enumeration of cytolytic effector cells
The numbers of B cells (CD19+), T cell (CD2+, CD3+, CD4+, CD8+) subsets, and NK cells (CD2+/CD3-, CD16+, CD56+) were determined by standard FACScan procedures with mAbs being produced by CLB (Amsterdam, The Netherlands). For determination of subpopulations within the CD8+ T cell fraction, FITC- and PerCP-conjugated CD8, CD27, and CD3 were all purchased from BD Biosciences (San Jose, CA). CD45RA-PE was obtained from Coulter Immunology (Hialeah, FL). Biotinylated CD27 was manufactured at CLB. Using these mAbs for triple staining, gating on CD8+ lymphocytes allowed further subtyping into naive resting cells (CD45RA+CD27+) and functional distinct subsets of primed cells, i.e., noncytolytic CD45RA-CD27+ (memory-type) and cytolytic CD45RA+CD27- T cells (effector-type), as extensively characterized previously (6, 7).
Generation of HLA-A2.1/CMVpp65(NLVPMVATV) and HLA-B7/CMVpp65(TPRVTGGGAM) tetrameric complexes
Tetrameric complexes were generated essentially as described by Altman et al. (23). In brief, purified HLA-A2.1 and HLA-B7 heavy chains and 
2 microglobulin were synthesized using a prokaryotic expression system (pET; Novagen, Milwaukee, WI). The heavy chains were modified by deletion of the transmembrane/cytosolic tail and COOH-terminal addition of a sequence containing the BirA enzymatic biotinylation site. The HLA-A2.1 binding CMV pp65-derived peptide NLVPMVATV and the HLA-B7 binding CMV pp65-derived peptide TPRVTGGGAM were used for refolding. The refolded products were isolated using HPLC, biotinylated by BirA (expressed using the pET expression system, purified using cobalt beads (Clontech, Palo Alto, CA)) in the presence of biotin (Molecular Probes, Eugene, OR), ATP (Sigma-Aldrich, St. Louis, MO), and MgCl. The biotinylated products were separated from free biotin by gel filtration using HPLC (24). Streptavidin-PE or streptavidin-allophycocyanin conjugate (Molecular Probes) was added in a 1/4 molar ratio.
Immunofluorescent staining and flow cytometry
Freshly isolated or thawed PBMC were resuspended in RPMI containing 10% FCS and antibiotics. PBMC (n = 200,000) were incubated with fluorescent label-conjugated mAbs (concentrations according to manufacturer’s instructions) and an appropriate concentration of tetrameric complexes in a small volume for 30 min at 4°C, protected from light. Cells were washed in PBS containing 0.01% (w/v) NaN3 and 0.5% (w/v) BSA. Analyses consisted of allophycocyanin-conjugated tetramers and CD8-PerCP (BD Biosciences) in combinations with CD45RA-FITC (BD Biosciences) and CD27-PE (BD Biosciences). Analysis of cells for the expression of cell surface markers was performed using a FACSCalibur flow cytometer and CellQuest software (BD Biosciences).
Statistics
Student’s t test and ANOVA were applied for normally distributed data, and the Wilcoxon two-sample test and the Kruskal-Wallis test were used for nonnormally distributed data. Fisher’s exact test was used for statistical analysis of symptoms in the cohorts of controls and patients.
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Results |
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Cohorts of patients are often compared with historic and/or presumably healthy controls, disregarding the potential impact of their infectious history. An additional problem arises because of the differences in lymphocyte numbers and lymphocyte subset distribution depending on age (25, 26). We performed an extensive immunophenotyping of PBMC from healthy children to define normal levels of predefined CD4+ and CD8+ T cell subpopulations in various age cohorts. In most of the children, serology (IgM and IgG) against EBV, CMV, VZV, and MMR was simultaneously performed. In this way we had the opportunity to analyze the relation between viral infections and immunization in the past, on the one hand, and the number of T cell subsets, on the other.
Absolute numbers of CD3+ lymphocytes, CD3- (CD16+CD56+) NK cells, and CD4+CD45RA+ and CD4+CD45R0+ T cells did not show a correlation of any kind with the serology findings against the viruses tested. However, a highly significant correlation was found between the percentage as well as the absolute number of circulating CD8+CD45RA+CD27- cytolytic T cells and CMV seropositivity in healthy individuals (Table II). Representative histograms of a CMV-seronegative and an age-matched CMV-seropositive individual (left and right panels, respectively) are shown in Fig. 1.
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CD8+CD45RA+CD27- T cells rise during acute CMV infection
Children without a known immune disorder of any kind who came to our attention because of acute CMV disease (n = 16) were studied. In two patients (Fig. 2, B and C) blood samples were available from a time point before the start of CMV disease. Acute disease was defined by positive cultures, CMV IgM serology, and, when performed, the presence of CMV DNA in whole blood as detected by a quantitative PCR technique (27). A progressive rise in CD8+CD45RA+CD27- T cell numbers was observed starting within 3–4 wk after diagnosis, which is in agreement with our recent observations in adults patients receiving allo-kidney grafts. Within 2 mo a plateau was reached, with stable numbers of CD8+CD45RA+CD27- T cells for the following months of follow-up (Fig. 2, A–C). Although in principle unselected, some bias in patient inclusion because of the presence of clinical symptoms of acute CMV disease at presentation cannot be excluded at this point. The variety of symptoms was diverse; some patients were admitted, while others were followed at the out-patient care unit.
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A genetic correlation with the absolute number of CD4+ and CD8+ T cells has been previously documented (30). The number at which a person’s CD8+ cytolytic T cells stabilize was investigated. Ten family pedigrees were tested for a pattern of segregation and gene inheritance (HLA class I and class II typing). As shown for three representative families (Fig. 4, A–C), the presence of CD8+CD45RA+CD27- T cells was unrelated to any of the viruses tested other than CMV, without a pattern of parental HLA haplotype inheritance (data not shown). Offspring from parents with high numbers of these cytolytic cells did not all show high numbers (Fig. 4B). Vice versa, children with high CD8+CD45RA+CD27- T cell numbers can have parents with low cytolytic T cell numbers (Fig. 4C). In some families one of the parents (mostly fathers (Fig. 4, B and C); rarely mothers (Fig. 4A)) was still CMV seronegative and did not have cytotoxic CD8+ T cells, whereas his/her partner and children showed positive reactivity.
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The set-point of CD8+CD45RA+CD27- T cells was only weakly related to age, whereas clinical symptoms during CMV infection, prior viral infections, racial background, and sex did not show any relation to the set-point (data not shown). When the two groupsmost separated in age were compared, a more direct age effect seemed apparent. Young children (age, 0–4 years; n = 23) and young adolescents (age, 15–18 years; n = 23) differed significantly in number and percentage of CD8+ cytolytic T cells also when the increased absolute number of CD8+ T cells at a young age was taken into account (Table IV).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of CMV in the selective expansion of particular CD8+ T cell subsets had been suggested (18, 31, 32); however, further phenotypic (apart from CD57) and functional characterization is lacking (31, 32). Moreover, the studies were performed in small cohorts of patients without long-term follow-up. It is unclear whether CD8+CD57+ T cells represent a unique and homogeneous subset with distinct functions. Using CD8+ T cells isolated from patients at various times after allogeneic bone marrow transplantation, high numbers of CD8+CD57+ T cells correlated with diminished killing of CMV-infected targets (33). Such a reduced cytotoxic capacity would support a functional relationship between immune competence (age, immunosuppression) and the number of CD8+CD45RA+CD27- cytolytic T cells (Fig. 5), of which most coexpress CD57 (9). In allogeneic transplants CD8+CD57+ T effector cells did not produce any TNF- or IFN- after anti-CD3 stimulation (33), whereas isolated CD8+CD45RA+CD27- T cells from healthy controls did (5). Moreover, the vast majority of resting CD8+ T cells capable of rapid induction of TNF- and IFN- synthesis in response to CMV peptides were found in a subset with intermediate to high expression of CD57, low CD27, and reversal of the classical memory CD45R0 to the CD45RA phenotype (34). This subpopulation probably includes the fully differentiated effector-type cells responsible for long term suppression of the virus and avoidance of disease from CMV reactivation. Using tetramer staining we found that these cells are generated at a relatively short time (2 mo) after primary CMV infection in children (Fig. 3C).
As we now demonstrate, CMV infection is the major trigger for the selective expansion of the CD8+CD45RA+CD27- T cell subset to an individual set-point at which the number of these CD8+ T cells stabilizes for the following years (Figs. 2 and 3). Of the various factors studied (such as race, sex, inheritance, coinfections (prior EBV, VZV, or MMR)), young age or immunosuppression at the onset of acute CMV infection determines to a large extent this individual set-point. An independent genetic impact on the number of T cells has been suggested (30). However, an inherited set-point for CD8+ cytolytic T cells after CMV infection was not supported by a study in 10 families, although the confounding factor age at onset of CMV infection was unknown for the families tested.
Speculations can be made about development of the cytotoxic CD8+ T cell subset. Although CD8+CD45RA+CD27- T cells are detected in all CMV-infected individuals, their numbers increase in clinical situations of immunosuppression (Fig. 5) (11). In immunosuppressed patients, CMV reactivation could still occur under relatively normal conditions (here evaluated by CD4+ T cell number and proliferation tests) during follow-up, allowing adaptive responses of the CD8+ T cell subsets to increased levels of viral Ag. Possibly CMV Ag not only induces further expansion of virus-specific cells, but also their development into CD8+CD45RA+CD27- T cells (28). The bulk of fully differentiated CD8+ T effector-type cells may, in fact, be different in specificity or binding avidity from the most potent cytotoxic T cells generated during CMV infection. CMV immunity in humans is focused on two immunodominant proteins, i.e., pp65 and, to a lesser extent, IE1 (35). Using the pp65 peptide-containing tetramer to detect CMV-specific T cells, we found that most of the CMV-tetramer positive cells (50–60%) were present in the CD8+CD45RA+CD27- T cell fraction, representing <10% of the total CD8+CD45RA+CD27- T cells (data not shown). Confirming data from adults (11), EBV-tetramer-positive cells (80–90%) predominated in CD45R0+CD27+ (memory-type) CD8+ T cell fraction (not shown). The restriction of EBV- and HIV-derived peptide-specific CD8+ T cells in adult patients to this type may very well represent a normal phenomenon (29).
The use of tetramers has, in just 4 years, transformed our understanding of the immune responses against HIV, human T lymphotrophic virus 1, hepatitis B and C virus, CMV, and EBV, and holds promise in a number of areas where quantitative analysis of the antiviral response in terms of both number and function is critical. Nevertheless, the technique remains limited in terms of suitability of the HLA background as well as availability of reagents to cover a more complete spectrum of protein-derived peptides involved in immunity. These techniques, however, leave open the question by which mechanism or protein(s) CMV induces the expansion of CD8+CD45RA+CD27- T cells.
In conclusion, we show that not only may CMV-specific cells preferentially have a CD8+CD45RA+CD27- phenotype, but, importantly, CMV is the predominant factor that determines the presence of these T cells in peripheral blood. The age at onset of CMV infection or, in more general terms, immunocompetence determines to a great extent the level or set-point at which an individual’s number of cytolytic cells stabilizes. The mechanism by which CMV induces a large number of uniquely expanded CD8+ cytolytic T cells warrants further study as an intriguing facet of the interplay between CMV and the immune system.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Taco W. Kuijpers, Emma Children’s Hospital, Academic Medical Center, Room G8-205, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: t.w.kuijpers{at}amc.uva.nl
3 Abbreviations used in this paper: VZV, varicella-zoster virus; MMR, measles-mumps-rubella.
Received for publication April 5, 2002. Accepted for publication February 7, 2003.
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producing CD4+ T cells in protection against CMV-disease. Blood In press.
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) and CD8+CD45RA+CD27- T cells (
) are compared with the CMV DNA concentration expressed as copies per milliliter of whole blood (•). Patient A was an infant treated with ganciclovir because of respiratory failure due to CMV pneumonitis; patients B and C were an untreated infant and a young child with symptoms of vomiting and temporary growth failure due to CMV hepatitis. Time zero represents retrospectively defined blood samples, once collected and preserved for other reasons. Data are representative for 16 patients in total.
).
